The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.
PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Although it is a complex process influenced by both physiological and psychological factors and is always subjective, its causes or syndromes can be classified. Pain can be classified based on temporal, aetiological or physiological criteria. When pain is classified by time, it can be acute or chronic. Aetiological classifications of pain are malignant or non-malignant. A third classification is physiological, which includes nociceptive pain (results from detection by specialized transducers in tissues attached to A-delta and C-fibers), that can be divided into somatic and visceral types of pain, and neuropathic pain (results from irritation or damage to the nervous system), that can be divided into peripheral and central neuropathic pain. Pain is a normal physiological reaction of the somatosensory system to noxious stimulation which alerts the individual to actual or potential tissue damage. It serves a protective function of informing us of injury or disease, and usually remits when healing is complete or the condition is cured. However, pain may result from a pathological state characterized by one or more of the following: pain in the absence of a noxious stimulus (spontaneous pain), increased duration of response to brief stimulation (ongoing pain or hyperpathia), reduced pain threshold (allodynia), increased responsiveness to suprathreshold stimulation (hyperalgesia), spread of pain and hyperalgesia to uninjured tissue (referred pain and secondary hyperalgesia), and abnormal sensations (e.g., dysesthesia, paresthesia).
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depression and other mood disorders that increase the levels of both serotonin and norepinephrine by inhibiting their reabsorption (reuptake) into cells in the CNS (Central Nervous System). There have been numerous studies demonstrating the analgesic effect of antidepressants, providing evidence that antidepressants are beneficial in the treatment of so-called ‘chronic pain’. The precise mechanisms involved in the pathogenesis of persistent pain states are not fully understood, but there is growing recognition that the disinhibition and imbalance of serotonin and norepinephrine in endogenous pain inhibitory pathways may contribute to persistent pain (Sussman, 2003; Marks et al., 2009).
Venlafaxine is the first and most commonly used SNRI. It was introduced by Wyeth in 1994. The reuptake effects of venlafaxine are dose-dependent. At low doses it acts only on serotonergic transmission, at moderate doses it acts on serotonergic and noradrenergic systems, whereas at high doses, it can also affect dopaminergic neurotransmission (Marks et al., 2009). Desvenlafaxine, Duloxetine, Milnacipram, Levomilnacipram, Sibutramine or Bicifadine are other known SNRIs, besides Venlafaxine.
Clinical indications of SNRIs include major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, neuropathic pain, fibromyalgia and chronical musculoskeletal pain.
There have been reported a number of side effects associated with SNRIs. The most common include loss of appetite, weight, and sleep. There may also be drowsiness, dizziness, fatigue, headache, increase in suicidal thoughts, emesis, nausea/vomiting, sexual dysfunction [including diminished interest in sex (libido) and difficulty reaching climax (anorgasmia)], and urinary retention. Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. People at risk for hypertension and heart disease should have their blood pressure monitored. Thus therapeutic utility of SNRIs is limited by undesirable adverse effects.
Two subtypes of Sigma receptors (Sigma-1 and Sigma-2 receptors) have been identified (Cobos et al., 2008). Confused with opioid receptors for many years due to the cross-reactivity of some ligands, the Sigma-1 receptor is a 24-kDa molecular mass protein of 223 amino acids anchored to the endoplasmic reticulum and plasma membranes (Cobos et al., 2008; Maurice and Su, 2009). Sigma-1 receptor is a unique ligand-regulated molecular chaperone which is activated under stress or pathological conditions and interacts with several neurotransmitter receptors and ion channels to modulate their function. The effects reported preclinically with Sigma-1 receptor ligands are consistent with a role for Sigma-1 receptor in central sensitization and pain hypersensitivity and suggest a potential therapeutic use of Sigma-1 receptor antagonists for the management of neuropathic pain as monotherapy (Romero et al., 2012).
Pyrazole derivatives of general formula (I) according to the present invention are described in WO 2006/021462 as compounds having pharmacological activity towards the sigma (σ) receptor useful, inter alia, in the prophylaxis and/or treatment of pain.
Pharmaceutical compositions (WO 2011/064296 A1), salts (WO 2011/064315 A1), polymorphs and solvates (WO 2011/095579 A1), and other solid forms (WO 2012/019984 A1) of said sigma ligands of formula (I) have been also disclosed as well as combinations with other active substances such a with opioids or opiates (WO 2009/130310 A1, WO 2012/016980 A2, WO 2012/072782 A1) or with chemotherapeutic drugs (WO 2011/018487 A1, WO 2011/144721 A1).
As mentioned above, therapeutic utility of SNRIs is limited by undesirable adverse effects including cardiovascular and gastrointestinal toxicity. Thus, strategies aimed to reduce doses needed for SNRIs indications, especially for analgesia, are desirable in order to improve their therapeutic window and extend their use in clinics.